Abstract
Abundant reactive gliosis and neuroinflammation are typical pathogenetic hallmarks of brains in Parkinson's disease (PD) patients, but regulation mechanisms are poorly understood. We are interested in role of programmed death-1 (PD-1) in glial reaction, neuroinflammation and neuronal injury in PD pathogenesis. Using PD mouse model and PD-1 knockout (KO) mice, we designed wild-type-control (WT-CON), WT-1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (WT-MPTP), PD-1-KO-control (KO-CON) and PD-1-KO-MPTP (KO-MPTP), and observed motor dysfunction of animal, morphological distribution of PD-1-positive cells, dopaminergic neuronal injury, glial activation and generation of inflammatory cytokines in midbrains by motor behavior detection, immunohistochemistry and western blot. WT-MPTP mouse model exhibited decrease of PD-1/Iba1-positive microglial cells in the substantia nigra compared with WT-CON mice. By comparison of four groups, PD-1 deficiency showed exacerbation in motor dysfunction of animals, decreased expression of TH protein and TH-positive neuronal protrusions. PD-1 deficiency enhanced microglial activation, production of proinflammatory cytokines like inducible nitric oxide synthase, tumor necrosis factor-α, interleukin-1β and interleukin-6, and expression and phosphorylation of AKT and ERK1/2 in the substantia nigra of MPTP model. We concluded that PD-1 deficiency could aggravate motor dysfunction of MPTP mouse model by inducing microglial activation and neuroinflammation in midbrains, suggesting that PD-1 signaling abnormality might be possibly involved in PD pathogenesis.
Highlights
Parkinson's disease (PD) is a common and severe neurodegenerative disease in the central nervous system (CNS) with high incidence that is just secondly to Alzheimer's disease (AD)
We concluded that Parkinson’s disease (PD)-1 deficiency could aggravate motor dysfunction of MPTP mouse model by inducing microglial activation and neuroinflammation in midbrains, suggesting that programmed death-1 (PD-1) signaling abnormality might be possibly involved in PD pathogenesis
Double immunofluorescence for Programmed death ligand 1 (PD-L1)/Iba1, PD-L1/glial fibrillary acidic protein (GFAP), and PD-L1/NeuN was performed to observe if any PD-L1, a PD-1 ligand, was localized in microglial cells, astrocytes and neurons, and data indicated that PD-L1 was mainly located in the microglial cells rather than astrocytes and neurons
Summary
Parkinson's disease (PD) is a common and severe neurodegenerative disease in the central nervous system (CNS) with high incidence that is just secondly to Alzheimer's disease (AD). Accumulating studies have shown that the neuroinflammation dominated by the activated glial cells, i.e. reactive microglial cells and astrocytes in the CNS, is involved in inducement and progression of dopaminergic neuronal degeneration in PD pathology [5,6,7,8]. The microglial cells and astrocytes function in protection of neurons by assisting synaptic transmission, removing dyed cell fragments or foreign harmful molecules, secreting neurotrophic factors and stabilizing microenvironment of CNS neurons [9,10,11]. Detailed significance of inflammatory response and related key regulation factors in modulating glial cell reaction or functional transition from congenital immunity to neuroinflammation state are still unclear [14, 15]
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